The goal of this clinical trial is to evaluate if phenserine can treat early or mild Alzheimer's Disease (AD) by comparing it to donepezil. This study will include participants with early or mild Alzheimer's Disease, and the main questions it aims to answer are:

How does phenserine affect exosome biomarkers of cell death compared to donepezil? What is the safety and tolerability profile of phenserine at ascending oral doses compared to donepezil? Researchers will compare participants receiving phenserine to those receiving donepezil to see if phenserine produces better pharmacodynamic outcomes and if it is safe and well-tolerated.

Participants will:

Be randomized to receive either oral phenserine or oral donepezil for a treatment duration of 8 weeks.

Undergo oral dose escalation based on tolerability. Complete regular follow-up visits every two weeks to assess pharmacodynamic, pharmacokinetic, and safety measures.

Participants will be randomized into two groups: one group will receive phenserine, and the other will receive donepezil. The phenserine group will begin with a dosage of 5 mg twice daily, with the dose being gradually increased every two weeks as tolerated with a maximum dose of 10 mg three times daily. The donepezil group will start at 5 mg once daily, with the possibility of escalation to 10 mg once daily at Week 4.

The study is designed to last 8 weeks, with a planned total enrollment of 16 individuals from various centers across Norway. Participants will return for follow-up visits every two weeks, during which pharmacodynamic, pharmacokinetic, and safety assessments will be conducted. The final safety follow-up will occur after the completion of dosing for those who complete the study. Early termination visits will include a comprehensive safety follow-up for those who discontinue the study prematurely.

The primary objective of this study is to assess the effects of phenserine compared to donepezil on exosome biomarkers of cell death in individuals with early or mild AD. Additionally, the study aims to evaluate the safety and tolerability profile of phenserine at ascending doses up to 10 mg three times daily (QDS) in comparison to donepezil at doses up to 10 mg once daily (OD). Furthermore, the study aims to analyze steady-state blood levels of phenserine to characterize and compare dose-response relationships for pharmacodynamic outcomes and key safety assessments. Finally, the study will explore changes in specific biomarkers of Alzheimer's Disease (AD) in cerebrospinal fluid (CSF) and blood plasma, as well as assess phenserine's potential short-term effects on cognition using the FLAME Memory Composite and other cognitive sub-tests.

Participants will be enrolled at six centers across Norway. The study will also be supported by the PROTECT platform, which allows for the recruitment of individuals over 50 years of age who have demonstrated cognitive decline, making them suitable candidates for this study.

The anticipated duration of participation for each patient is 8 weeks, with the overall study expected to be completed within 9 months, accounting for a 6-month enrollment period followed by the treatment phase.

Study Population and Statistical Methods

A total of 16 participants are expected to be enrolled in this dose-ranging study. The primary population for analysis will be a modified intent-to-treat group, including all participants who received at least one dose of study medication and provided at least one follow-up exosome sample.

This study will provide critical data on the pharmacodynamic and pharmacokinetic profiles of phenserine, which will guide future research and potential therapeutic strategies for early to mild AD.

Background

In 2018, and in parallel with the conduct of the ELAD study that evaluated liraglutide (an established medication for Type 2 diabetes) for its neuroprotective effects in people with mild to moderate AD, we initiated a new selection process to identify additional drug candidates for re-purposing in AD, MCI and other forms of dementia. Drug repurposing, defined as "the application of established drug compounds to new therapeutic indications," offers a route to drug development that is accessible to academic institutions, government and research council programs, and charities and not-for-profit organizations, complementing the work of pharmaceutical and biotechnology companies. Repurposing an existing drug offers an attractive way of enhancing traditional drug development and accelerating new treatments for people with AD dementia and MCI into the clinic.

The international expert panel that participated in the 2018 assessment applied the same approach as in the earlier 2012 selection process. A total of five compounds or classes of compounds were nominated for further consideration by the panel. These compounds were ACE inhibitors, antiviral drugs, disease-modifying antirheumatic drugs (DMARDs), fasudil and phenserine. Following several rounds of prioritization, the panel came to a clear consensus that the three highest priority candidates for repurposing in AD, MCI and other dementias were phenserine, fasudil, and antiviral drugs. This protocol is designed to assess the safety and tolerability of phenserine compared to donepezil across a range of doses administered over a 8-week dosing period in participants with early or mild AD. The pharmacodynamic and pharmacokinetic activity of the two drugs will also be evaluated to determine dose-response relationships to identify an appropriate dose range for a subsequent Phase 2 study of phenserine.

Phenserine was initially developed as an acetylcholinesterase inhibitor (AChEI) , but there are several mechanisms by which phenserine may act on neuronal and synaptic loss , a key common pathway evident in AD. A range of pre-clinical studies indicate that phenserine suppresses interleukin-1b, reduces glutamate-induced excitotoxicity, protects against oxidative toxicity, reduces A-beta levels, improves neural precursor cell viability, elevates neurotrophic brain-derived neurotrophic factor, and inhibits amyloid-beta precursor protein synthesis. In the only published phase 2 randomized controlled trial (RCT), phenserine (10-15 mg b.i.d.) conferred improvement in cognition in people with AD receiving 12 weeks of the higher dose of phenserine. Safety and tolerability were very good. The proportion of withdrawals due to adverse events was 6% in the placebo arm and the highest dose groups, indicating that the optimal dose was probably not achieved for most patients. There were also methodological problems, prompting the authors to conclude that the full potential of phenserine for AD has not yet been fully evaluated.

The most common side-effects of phenserine are those associated with cholinesterase inhibition, i.e., nausea, vomiting and diarrhoea. The best predictor of cholinesterase linked gastrointestinal effects is the level of cholinesterase inhibition achieved, with the optimal therapeutic threshold being 50% inhibition. Given that the completed clinical trials with phenserine did not select patients based on biomarker confirmation of AD (meaning that a considerable proportion of participants likely did not have AD), and that the maximum dose did not lead to side-effects and thus many participants did not likely achieve a sufficiently high dose level, this study aims to evaluate the effects of an individualized maximum tolerated phenserine dose with adequate level of AChE inhibition to determine an appropriate dose range for subsequent efficacy trials.

Inclusion Criteria:

• A diagnosis of AD based on the most recent NIA-AA diagnostic criteria for AD.
• A significant change on a validated AD amyloid or tau biomarker (as determined either by visual reading of amyloid PET scans [using any of the approved ligands], or CSF Aβ 1-42 or blood p-tau 217 levels [cut-off as determined by the individual laboratory.
• A CDR Global rating of 0.5 or 1.0.
• An MRI scan within the past two years that has no findings inconsistent with AD.
• Participants who have recently participated in other clinical trials or have been under treatment with memantine or acetylcholinesterase inhibitors (e.g., Donepezil, Rivastigmine, Galantamine) must undergo a washout period of at least 4 weeks prior to the start of the study.
• Capacity to give informed consent based on the clinical judgement of an experienced clinician.
• The participant has an individual who is in regular, daily contact via phone or in-person visits and who can act as a reliable study partner and provide meaningful input into rating scales.
• Age ≥50 years.
• Fluency in Norwegian and evidence of adequate premorbid intellectual functioning.
• Capable of participating in all scheduled evaluations and complete all required tests.
• Female participants must be of non-childbearing potential or have a negative serum pregnancy test up to 24 hours prior to the baseline assessments and agree to use effective birth control throughout their participation in the study from signing informed consent form until at least 30 days after last administration of phenserine or donepezil..

Exclusion Criteria:

• Significant cerebrovascular disease, as indicated by clinical history, neurological examination, or on MRI (including cortical infarction or deep white matter or periventricular white matter hyperintensities with a Fazekas scale score of 3 (25).
• Current treatment with a cholinesterase inhibitor or memantine.
• Hypersensitivity to AChE inhibitors or related compounds: Known hypersensitivity to donepezil, piperidine derivatives, or any formulation components.
• Participants undergoing or planning procedures requiring anesthesia with depolarizing neuromuscular blockers (e.g., succinylcholine) due to the risk of prolonged paralysis or apnea when combined with AChE inhibitors.
• Active peptic ulcer disease or gastrointestinal bleeding, or a history of gastrointestinal ulcers or bleeding.
• Severe cardiac conditions: Significant arrhythmias, sick sinus syndrome, supraventricular conduction abnormalities, or other cardiac rhythm disorders that could pose a risk with cholinesterase inhibitors.
• Severe respiratory disease: Chronic obstructive pulmonary disease (COPD) or poorly controlled asthma.
• History of urinary obstruction or bladder issues, particularly those requiring catheterization.
• Current clinically significant depression or other mental disorders likely to affect cognition or interfere with study participation.
• Participants using sedating drugs, if unavoidable, will be excluded from the study. However, short-acting sleep medications can be used if taken as recommended and if the participant has maintained a stable regimen for at least 3 months prior to the start of the study.
• Current participation in any other drug trial(s).
• Currently ongoing life-threatening disease, such as metastatic cancer, advanced cardiovascular disease, advanced respiratory disease, terminal kidney disease, or advanced stages of an infectious disease.
• Any current or past neurological disease unrelated to AD and with cognitive sequelae.](streamdown:incomplete-link)